Luteinizing hormone releasing hormone (LHRH) is released from the hypothalamus and binds to a receptor on the anterior pituitary gland causing the release of gonadotropin hormones. The gonadotropin hormones, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), secreted from the anterior pituitary gland, regulate fundamental reproductive processes, such as ovarian release and gamete maturation. These play a major role in regulating the synthesis of the steroidal reproductive hormones from the gonads, ie. estrogen and progesterone in females and testosterone in males.
The ongoing system of feedback between hypothalamus, the anterior pituitary gland, and the gonads modulates the fundamental processes related to the reproductive cycle. The feedback process, described by A. V. Schally et al., Fertility and Sterility, 22:11 (1971), provides a web of complex relationships related to reproductive functions. Pulsatile release of the gonadotropin hormones controls levels of steroidal hormone circulating in the mammalian reproductive cycle. Manipulation of the release of these hormones provides an avenue for the design of novel agents useful in treating various conditions related to dysfunction of the reproductive cycle and hormone dependent diseases. Several agonists of natural LHRH have been shown to be clinically useful.
Natural mammalian releasing hormone LHRH isolated and purified from porcine and human hypothalami has been characterized as having the sequence:
(Pyro)Glu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH.sub.2 PA1 R.sup.1 is of the formula R.sup.3 (C.dbd.O)--, wherein R.sup.3 is lower alkyl; PA1 A is an amino acyl residue selected from the group consisting of: PA1 B is an amino acyl residue selected from the group consisting of: PA1 C is an amino acyl residue selected from the group consisting of: PA1 D is seryl; PA1 E is an acyl group selected from the group consisting of: PA1 F is an amino acyl residue selected from the group consisting of: PA1 G is an amino acyl residue selected from the group consisting of: PA1 R.sup.2 is of the formula --NR.sup.4 R.sup.5 ; wherein PA1 R.sup.4 is selected from the group consisting of: PA1 R.sup.5 is selected from the group consisting of: PA1 R.sup.6 is selected from the group consisting of amino, guanidino, hydrogen, hydroxy, phenyl, morpholinyl, piperidinyl, pyrrolyl, pyridyl, pyrrolidinyl, pyrrolidinonyl, and quinuclidinyl; and wherein the piperidinyl, pyrrolyl, pyrrolidinyl, and pyrrolidinonyl groups are optionally substituted with a methyl group. PA1 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH-nBu; PA1 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.2 NH.sub.2 ; PA1 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.2 -(1-pyrrolidine); PA1 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-N(CH.sub.2 CH.sub.3).sub.2 ; PA1 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.6 NH.sub.2 ; PA1 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.4 NH.sub.2 ; PA1 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.2 OH; PA1 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.2 -phenyl; PA1 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.2 NH-isopropyl; PA1 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.7 NH.sub.2 ; PA1 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.6 NH(C.dbd.NH)NH.sub.2 ; PA1 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.5 NH-isopropyl; PA1 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.5 NH.sub.2 ; PA1 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.5 NH(C.dbd.NH)NH.sub.2 ; PA1 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.3 NH.sub.2 ; PA1 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.2 NH(C.dbd.NH)NH.sub.2 ; PA1 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.10 NH.sub.2 ; PA1 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.8 NH.sub.2 ; PA1 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.2 NHCH.sub.3 ; PA1 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.8 NH(C.dbd.NH)NH.sub.2 ; PA1 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.10 NH-isopropyl; PA1 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.4 NH(C.dbd.NH)NH.sub.2 ; PA1 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.4 NH(C.dbd.NH)NH.sub.2 ; PA1 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--CH.sub.2 -(2-pyridine); PA1 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--CH.sub.2 -(3-pyridine); PA1 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(3-quinuclidine); PA1 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--CH.sub.2 CH.sub.2 -(1-piperidine); PA1 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--CH.sub.2 CH.sub.2 -(1-morpholine); PA1 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--CH.sub.2 CH.sub.2 -(2-pyridine); PA1 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--CH.sub.2 CH.sub.2 -[2-(1-methyl)pyrrole]; PA1 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--CH.sub.2 CH.sub.2 -[2-(1-methyl)pyrrolidine]; PA1 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--CH.sub.2 CH.sub.2 CH.sub.2 -(1-morpholine); PA1 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--CH.sub.2 CH.sub.2 CH.sub.2 --N[(2-methyl)piperidine]; PA1 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--CH.sub.2 CH.sub.2 CH.sub.2 -(1-pyrrolidin-2-one); PA1 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--CH.sub.2 CH.sub.2 --CH.sub.2 CH.sub.2 OH; PA1 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH(CH.sub.2).sub.9 NH.sub.2 ; PA1 NAcD2Nal-D4ClPhe-D3Pal-Ser-Tyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.2 -(1-pyrrolidine); PA1 NAcD2Nal-D4ClPhe-D3Pal-Ser-Tyr-DCit-Leu-NH--(CH.sub.2).sub.2 -(1-pyrrolidine); PA1 NAcD2Nal-D4ClPhe-D3Pal-Ser-Tyr-DCit-Leu-NH--(CH.sub.2).sub.2 -(1-pyrrolidine); PA1 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DCit-Leu-NH--(CH.sub.2).sub.2 -(1-pyrrolidine); PA1 NAcD2Nal-D4ClPhe-D3Pal-Ser-DLys(Nic)-DLys(Nic)-Leu-NH--(CH.sub.2).sub.2 -(1-pyrrolidine); PA1 NAcD2Nal-D4ClPhe-D3Pal-Ser-Arg-DTrp-Leu-NH--(CH.sub.2).sub.2 -(1-pyrrolidine); PA1 NAcD2Nal-D4ClPhe-D3Pal-Ser-Tic-DLys(Nic)-Leu-NH--(CH.sub.2).sub.2 -(1-pyrrolidine); PA1 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMePhe-DLys(Nic)-Leu-NH--(CH.sub.2).sub.2 -(1-pyrrolidine); PA1 NAcSar-D4ClPhe-D1Nal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.2 -(1-pyrrolidine); PA1 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DArg-Leu-NH--(CH.sub.2).sub.2 -(1-pyrrolidine); PA1 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMePhe(4-NAc)-DPhe(4-NAc)-Leu-NH--(CH.sub.2). sub.2 -(1-pyrrolidine); PA1 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMePhe(4-NO.sub.2)-DCit-Leu-NH--(CH.sub.2).sub.2 -(1-pyrrolidine); PA1 NAcD2Nal-D4ClPhe-D3Pal-Ser-Phe(4-Atza)-DPhe(4-Atza)-Leu-NH--(CH.sub.2).sub. 2 -(1-pyrrolidine); PA1 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMePhe(4-Atza)-DPhe(4-Atza)-Leu-NH--(CH.sub.2). sub.2 -(1-pyrrolidine); and PA1 NAcD2Nal-D4ClPhe-D3Pal-Ser-Phe(4-NAc)-DPhe(4-NAc)-Leu-NH--(CH.sub.2).sub.2 -(1-pyrrolidine).
as described in A. V. Schally, Science, 202:6 (1978). Substitutions and derivatizations of amino acyl residues have been developed to achieve novel compounds useful in treating various disorders related to mammalian reproductive systems.
Synthetic analogs of LHRH have been described in a number of U.S. patents for exhibiting activity as LHRH agonists or as antagonists of LHRH. For the most part, these compounds contain nine or ten amino acyl residues, substituting naturally-occurring or non-naturally occurring amino acid residues at one or more positions in the natural sequence of LHRH. U.S. Pat. No. 5,110,904 describes nonapeptide and decapeptide LHRH antagonists wherein the nitrogen atom of at least one of the amide bonds has been alkylated. The decapeptide and undecapeptide analogs described in U.S. Pat. No. 5,502,035 have an acyl-substituted N-terminal nitrogen atom.
Truncated peptide compounds have been developed as series of smaller peptide analogs also exhibiting biological activity and having the added advantage of possibly improved oral bioavailability. These reduced-size peptides, described in U.S. Pat. No. 5,140,009, exhibit effective LHRH agonist or antagonist activity. They are "pseudo" hexapeptide, heptapeptide, octapeptide and nonapeptide analogs of LHRH, which have 1 to 3 amino acids eliminated from the N-terminus of a decapeptide antagonist sequence to achieve activity as LHRH antagonists. Distinctively, the peptides described in this invention have the 10 to 8 amino acids eliminated from the C-terminus. Copending U.S. application Ser. No. 09/373,180 discloses and claims a class of pentapeptide LHRH analogs wherein the 1 to 3 amino acids are eliminated from the N-terminus and the 10 to 8 amino acids from the C-terminus of a decapeptide LHRH antagonist.
The development of synthetic LHRH antagonists truncated from the C-terminus having biological activity provides novel compounds for treatment of hormone dependent diseases in male and female mammals. Smaller synthetic peptide sequences provide significant advantages when compared to decapeptide LHRH analogs. These LHRH antagonists are useful in the treatment of a variety of clinical condition in which the suppression of sex steroids plays a major therapeutic role, including delay of puberty, treatment of benign prostatic hyperplasia, palliative treatment or remission of hormonal-dependent tumors of breast and ovaries, palliative treatment or remission of hormonal-dependent tumors of the prostate, the treatment of cryptorchidism, hirsutism in women, gastric motility disorders, dysmenorrhea, and endometriosis.